31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

The Lengthened Shadow of Another Institution? Ideal Point Estimates for the Executive Branch and Congress

While the president's relationship to Congress has been carefully studied, the broader executive branch has received far less attention in that context. Scholars rely on assumptions about the relationship between the president and cabinet departments that remain untested. We construct the first statistical portrait of executive branch ideology by estimating ideal points for members of Congress, presidents, and the heads of cabinet‐level departments between 1991 and 2004 in a Bayesian framework. We empirically assess claims about the composition of the president's administrative team and the influence of institutions on the ideology of principal executive decision makers. We also test an important claim regarding the trade‐off between ideological congruence and budgetary authority to demonstrate the utility of our estimates for other scholars. Our analysis reveals a new picture of the executive branch as ideologically diverse, casting into doubt some essential assumptions in a substantial body of work on the separation of powers

Random Audits and Regulatory Compliance

Rigorous policy evaluation often involves randomization, and both federal and state governments have used randomization for a variety of purposes for approximately two centuries. But in the particular context of random government audits, transparency of process is crucial—especially when non-compliance can have reputational effects. One of the first recorded government randomizations was by states in the early 1800s. It involved the shameful removal of indigenous people from their land followed by distribution of that same land to white people via land lottery. Other randomizations over time have included diversity visa lotteries, the draft lottery for selective military service, and education lotteries to place students in public schools. Panels of judges are often randomly assigned to review cases, and administrators on some government boards are also randomly assigned to make decisions. Randomizations for policy evaluation are now so common that the U.S. General Services Administration has an Office of Evaluation Sciences that has conducted over 70 randomized policy experiments. Governments also regularly conduct audits, some random and some not. Examples include audits of financial records by the U.S. Securities and Exchange Commission, random audits of lobbying disclosures by the U.S. Government Accountability Office (GAO), audits of federal taxpayers to assess compliance with the Internal Revenue Code, and randomized review of Board of Veterans’ Appeals opinions for quality control. Those audited include regular citizens, firms, agencies, policies, lobbyists, and even elected officials. As we explain in a recent article published in the journal Public Choice, government regulators may want to conduct random audits for several reasons. First, random audits are a fair method of allocating resources. Assuming that regulators are not able to audit all entities of interest, random audits allow every potential person or firm subject to audit to have a similar probability of being audited. Second, random audits by government agencies are effective policy tools to encourage regulatory compliance. In addition, ongoing random audits may allow for longer-term equilibrium effects to emerge, as people and entities select into or out of the regulatory regime because the audits raise the costs of both compliance and non-compliance. Third, randomization by government agencies allows for policy evaluation: Are regulatory policies working as intended? Do the incentives embedded within policies change behavior? Audits can also allow regulators to test the outcome of policies that may have unintended effects. Before a full launch of a new regulatory policy, piloting the policy on a randomly selected subset of intended program members allows policymakers to refine the policy—or abort it—before the final launch. One random audit of particular interest is the Federal Election Commission’s (FEC) random auditing of campaigns for the U.S. House of Representatives and U.S. Senate following the 1976 elections. The FEC made a series of decisions in its rollout of the audits. First, it decided to do random audits in the first place. As a retired auditor who was present at the time told us, when the FEC was created, former GAO auditors then at the FEC assumed they would conduct audits, simply because they had always audited all Senate campaigns while at GAO. Of course, the House of Representatives is much bigger than the Senate, so the auditors knew their resources would never permit them to audit all campaigns for House districts. Guided by their prior experience, they decided that they could audit 10 percent of House seats after every election. But how to select them? Fairness dictated random selection, and so they used a computer-based randomizer and selected 10 percent of House seats to audit. Evidence from local newspaper reporting indicates that the FEC communicated information about the audits in a confusing way. It reassured journalists who inquired about the audits that they were routine in nature, but it did not release a list of seats chosen for audit to inquiring journalists after the drawing occurred. Perhaps the FEC wanted audited candidates to control the information about the audits—after all, once the results were all in, 43 percent of the audits uncovered violations of the brand-new campaign finance rules. Publicizing that a member of the House of Representatives had been selected for random audit would have given local journalists an invitation to follow up on the results of the audit, potentially exposing the member to a scandal. But the choice to disclose the names of the audited members only when the audits were completed—in most cases, months after the random draw—came with a downside. Inattentive constituents might have assumed that audits were conducted based on suspicion of malfeasance, endangering the electoral fortunes of the 57 percent of randomly selected members whose audits uncovered no campaign finance violations. Electoral regulators are in a particularly vulnerable institutional position, as their appropriations and oversight levels are determined by the people they regulate. Sure enough, the FEC soon found itself on the defensive in oversight hearings on Capitol Hill. The hearing transcripts reveal that some members of the committee found the audits to be annoying and questioned the randomization itself. Unsurprisingly, the audit program was defunded going forward. The FEC’s rollout of the audits may have been important to the program’s eventual defunding. But it is possible that the failure to disclose the list of seats selected for random audit made voters less likely to believe that the audits were routine. The experience of the Fair Political Practices Commission (FPPC), California’s campaign finance regulator, may be instructive for electoral agencies planning random audits in the future. The FPPC regulates money in California politics, and it uses random audits to encourage compliance and uncover noncompliance. But its audit procedures are more transparent than the procedures the FEC used in the 1970s, and the differences probably help minimize the negative impact of being audited in California. Most importantly, the FPPC conducts the random drawings in public and lists the selections on its website. Government randomization has a long history and is growing increasingly common. When a government conducts random audits whose results present reputational risks to the subjects, program rollout is important. Policymakers planning random audits would be well-served to follow the lead of California’s FPPC by conducting randomized audits in the sunlight, allowing those selected for audit to show that their audit truly is routine in nature

Random Audits and Regulatory Compliance

Rigorous policy evaluation often involves randomization, and both federal and state governments have used randomization for a variety of purposes for approximately two centuries. But in the particular context of random government audits, transparency of process is crucial—especially when non-compliance can have reputational effects. One of the first recorded government randomizations was by states in the early 1800s. It involved the shameful removal of indigenous people from their land followed by distribution of that same land to white people via land lottery. Other randomizations over time have included diversity visa lotteries, the draft lottery for selective military service, and education lotteries to place students in public schools. Panels of judges are often randomly assigned to review cases, and administrators on some government boards are also randomly assigned to make decisions. Randomizations for policy evaluation are now so common that the U.S. General Services Administration has an Office of Evaluation Sciences that has conducted over 70 randomized policy experiments. Governments also regularly conduct audits, some random and some not. Examples include audits of financial records by the U.S. Securities and Exchange Commission, random audits of lobbying disclosures by the U.S. Government Accountability Office (GAO), audits of federal taxpayers to assess compliance with the Internal Revenue Code, and randomized review of Board of Veterans’ Appeals opinions for quality control. Those audited include regular citizens, firms, agencies, policies, lobbyists, and even elected officials. As we explain in a recent article published in the journal Public Choice, government regulators may want to conduct random audits for several reasons. First, random audits are a fair method of allocating resources. Assuming that regulators are not able to audit all entities of interest, random audits allow every potential person or firm subject to audit to have a similar probability of being audited. Second, random audits by government agencies are effective policy tools to encourage regulatory compliance. In addition, ongoing random audits may allow for longer-term equilibrium effects to emerge, as people and entities select into or out of the regulatory regime because the audits raise the costs of both compliance and non-compliance. Third, randomization by government agencies allows for policy evaluation: Are regulatory policies working as intended? Do the incentives embedded within policies change behavior? Audits can also allow regulators to test the outcome of policies that may have unintended effects. Before a full launch of a new regulatory policy, piloting the policy on a randomly selected subset of intended program members allows policymakers to refine the policy—or abort it—before the final launch. One random audit of particular interest is the Federal Election Commission’s (FEC) random auditing of campaigns for the U.S. House of Representatives and U.S. Senate following the 1976 elections. The FEC made a series of decisions in its rollout of the audits. First, it decided to do random audits in the first place. As a retired auditor who was present at the time told us, when the FEC was created, former GAO auditors then at the FEC assumed they would conduct audits, simply because they had always audited all Senate campaigns while at GAO. Of course, the House of Representatives is much bigger than the Senate, so the auditors knew their resources would never permit them to audit all campaigns for House districts. Guided by their prior experience, they decided that they could audit 10 percent of House seats after every election. But how to select them? Fairness dictated random selection, and so they used a computer-based randomizer and selected 10 percent of House seats to audit. Evidence from local newspaper reporting indicates that the FEC communicated information about the audits in a confusing way. It reassured journalists who inquired about the audits that they were routine in nature, but it did not release a list of seats chosen for audit to inquiring journalists after the drawing occurred. Perhaps the FEC wanted audited candidates to control the information about the audits—after all, once the results were all in, 43 percent of the audits uncovered violations of the brand-new campaign finance rules. Publicizing that a member of the House of Representatives had been selected for random audit would have given local journalists an invitation to follow up on the results of the audit, potentially exposing the member to a scandal. But the choice to disclose the names of the audited members only when the audits were completed—in most cases, months after the random draw—came with a downside. Inattentive constituents might have assumed that audits were conducted based on suspicion of malfeasance, endangering the electoral fortunes of the 57 percent of randomly selected members whose audits uncovered no campaign finance violations. Electoral regulators are in a particularly vulnerable institutional position, as their appropriations and oversight levels are determined by the people they regulate. Sure enough, the FEC soon found itself on the defensive in oversight hearings on Capitol Hill. The hearing transcripts reveal that some members of the committee found the audits to be annoying and questioned the randomization itself. Unsurprisingly, the audit program was defunded going forward. The FEC’s rollout of the audits may have been important to the program’s eventual defunding. But it is possible that the failure to disclose the list of seats selected for random audit made voters less likely to believe that the audits were routine. The experience of the Fair Political Practices Commission (FPPC), California’s campaign finance regulator, may be instructive for electoral agencies planning random audits in the future. The FPPC regulates money in California politics, and it uses random audits to encourage compliance and uncover noncompliance. But its audit procedures are more transparent than the procedures the FEC used in the 1970s, and the differences probably help minimize the negative impact of being audited in California. Most importantly, the FPPC conducts the random drawings in public and lists the selections on its website. Government randomization has a long history and is growing increasingly common. When a government conducts random audits whose results present reputational risks to the subjects, program rollout is important. Policymakers planning random audits would be well-served to follow the lead of California’s FPPC by conducting randomized audits in the sunlight, allowing those selected for audit to show that their audit truly is routine in nature

Secretaries of Pork? A New Theory of Distributive Public Policy

Scholars have focused attention toward congressional influence over distributive grant allocations, but they have less frequently examined the extent to which administrative agencies play a role in that process. We present a new theory of ideology-contingent executive decision making within a multiple-principals framework to explain the geographic distribution of policy benefits. Our theory is novel in that it locates interbranch ideological conflict and confluence at the center of bureaus’ allocational strategies. Discretionary Department of Labor (DOL) grants and Department of Defense (DOD) contracts from 1991 to 2002 are examined to provide evidence that agencies deliver more grants to senators with proximate ideologies. To measure bureaucratic ideology, we generate comparable ideology estimates for cabinet secretaries, presidents, and members of the U.S. Senate via an item-response model. Our findings suggest that ideological congruence between senators and DOL or DOD is associated with significantly larger amounts of grants or contracts, respectively. These findings are important as they recast our understanding of distributive politics into ideological terms

Agreeable administrators? Analyzing the public positions of cabinet secretaries and presidents

Cabinet secretaries represent their departments when testifying before Congress on a broad range of legislation. Do they also represent the president's views on such legislation? Consistent with institutional theories of the presidency, we posit that, in some instances, cabinet secretaries take public positions contrary to those of the president, suggesting ideological distinctions between presidents and their appointed secretaries. We examine all congressional testimonies of secretaries of labor, commerce, and agriculture from 1991 to 2002, coding their positions taken on legislation considered on the floor of the Senate. Though these public disagreements are infrequent, our evidence suggests that agreement is more likely as support for the president's position among oversight committee members increases, yet less likely as secretaries’ tenure in office increases

The spatial model and the Senate trial of President Clinton

Most accounts of the Clinton Senate trial are based on legal theories and description or suggest that the Senate trial was sui generis, unrelated to regular Senate business. Alternatively, we argue that presidential removal trials can best be explained through a spatial voting model, with ideological estimates for senators best predicting the trial outcome. To examine these hypotheses, we generate (a) ideal-point estimates using Markov chain Monte Carlo methods on roll-call data as well as (b) text-based (wordscores) point estimates scaled from public statements. Our results support the spatial hypothesis, but not legal or idiosyncratic accounts. Moreover, the significant discrepancy between text- and vote-based estimates provides support for Mayhew’s contention that position taking for constituency benefit is rather costless. We conclude that when asked to be judges, senators, faced with multifarious political incentives, are more likely to act like legislators